Ignite Creation Date:
2024-05-06 @ 10:05 AM
Last Modification Date:
2024-10-26 @ 12:24 PM
Study NCT ID:
NCT03156036
Status:
COMPLETED
Last Update Posted:
2023-09-07
First Post:
2017-05-03
Brief Title:
Preoperative CRT With Capecitabine Temozolomide in Patients With LARC
Sponsor:
Asan Medical Center
Organization:
Asan Medical Center
Study Overview
Official Title:
Preoperative Chemoradiotherapy With Capecitabine With or Without Temozolomide in Patients With Locally Advanced Rectal Cancer A Prospective Randomised Phase 2 Study Stratified by MGMT O6-methylguanine DNA Methyltransferase Status
Status:
COMPLETED
Status Verified Date:
2023-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is a prospective biomarker-stratified randomised phase II study of preoperative CRT with temozolomide plus capecitabine in patients with locally advanced rectal cancer
The primary endpoint is pathologic complete response rates defined as total regression of the primary tumor
For each cohort of MGMT hypermethylated versus MGMT unmethylated patients will be randomised ratio 11 for each arm into preoperative CRT with capecitabine or preoperative CRT with temozolomide plus capecitabine arms According to the prior phase I results MGMT hypermethylated arm is estimated as 70 of total patients and the target pathologic complete response rate was assumed as 35 in this population when treated with preoperative CRT with temozolomide and capecitabine 15 in the standard treatment arm or those with unmethylated MGMT Investigator would like to demonstrate the superiority in terms of pathologic complete responses when treated with preoperative CRT with temozolomide plus capecitabine in patients with locally advanced rectal cancer and to validate the predictive role of MGMT status
The primary endpoint is pathologic complete response rates defined as total regression of the primary tumor
For each cohort of MGMT hypermethylated versus MGMT unmethylated patients will be randomised ratio 11 for each arm into preoperative CRT with capecitabine or preoperative CRT with temozolomide plus capecitabine arms According to the prior phase I results MGMT hypermethylated arm is estimated as 70 of total patients and the target pathologic complete response rate was assumed as 35 in this population when treated with preoperative CRT with temozolomide and capecitabine 15 in the standard treatment arm or those with unmethylated MGMT Investigator would like to demonstrate the superiority in terms of pathologic complete responses when treated with preoperative CRT with temozolomide plus capecitabine in patients with locally advanced rectal cancer and to validate the predictive role of MGMT status
Detailed Description:
Preoperative chemoradiation CRT with fluoropyrimidine 5-fluorouracil or capecitabine is now regarded as a standard treatment option in patients with locally advanced resectable rectal cancer and pathologic response rates and tumor regression grades after preoperative CRT have been proved to be important prognostic factors for survival outcomes
Several studies of preoperative CRT with fluoropyrimidines plus other agents such as oxaliplatin irinotecan cetuximab and bevacizumab have been performed to improve pathologic response rates however they have failed to show improved results compared to those with fluoropyrimidine alone
Thus fluoropyrimidine alone is a standard chemotherapeutic strategy in patients with locally advanced resectable rectal cancer who will be treated with preoperative CRT at present
Temozolomide is an oral alkylating agent and has been proved to be effective in patients with glioblastoma or high grade anaplastic glioma when administered with concurrent radiotherapy either as adjuvant or recurrent settings
Temozolomide has been known to deplete O6-methylguanine DNA methyltransferase MGMT which is one of the DNA repair enzymes and recent studies have shown that MGMT gene silencing lower expression by immunohistochemistry or hypermethylation by methylation-specific PCR played a predictive marker of better responses to CRT with temozolomide in patient with glioblastoma and high grade anaplastic glioma
Silencing of MGMT by promoter hypermethylation has been known to involve colorectal carcinogenesis pathway by the association with KRAS mutation and low-CIMP CpG island methylation phenotype and microsatellite instability There have been suggestions that MGMT promoter hypermethylation played a role as a predictive factor of low recurrence in colorectal cancer patients with adjuvant oral fluoropyrimidine chemotherapy after curative surgery and also as a predictive factor for treatment response from temozolomide in patients with metastatic colorectal cancer
Therefore combination chemotherapy of temozolomide plus capecitabine for rectal cancer patients when treated with preoperative CRT is worthy of investigated especially in those harbouring silenced MGMT gene as following reasons
1 the role of temozolomide has been well established
2 MGMT gene silencing is associated with colorectal carcinogenesis and might act as a predictive biomarker and
3 the addition of temozolomide can be synergistic during preoperative CRT with capecitabine for rectal cancer patients
Investigator have performed a phase I study of preoperative CRT with temozolomide plus capecitabine in patient with locally advanced rectal cancer and the results of this study has been published The recommended dose of temozolomide was determined as 75 mgm2 once daily when combined with standard preoperative CRT with capecitabine there was no grade 4 adverse events and the treatment was generally well tolerated MGMT hypermethylation was found in 72 of rectal cancer patients 1622 and the pathologic complete responses rates were 375 616 in patient harbouring hypermethylated MGMT versus 167 in those with unmethylated MGMT
On the basis of prior trial results Investigator concluded that preoperative CRT with temozolomide plus capecitabine is well tolerated without any notable adverse event and is worthy of investigation especially in those harbouring MGMT gene silencing
Investigator planned a prospective biomarker-stratified randomised phase II study of preoperative CRT with temozolomide plus capecitabine in patients with locally advanced rectal cancer to demonstrate the addition of temozolomide in the conventional preoperative CRT might enhance the pathologic responses in those harbouring hypermethylated MGMT
Several studies of preoperative CRT with fluoropyrimidines plus other agents such as oxaliplatin irinotecan cetuximab and bevacizumab have been performed to improve pathologic response rates however they have failed to show improved results compared to those with fluoropyrimidine alone
Thus fluoropyrimidine alone is a standard chemotherapeutic strategy in patients with locally advanced resectable rectal cancer who will be treated with preoperative CRT at present
Temozolomide is an oral alkylating agent and has been proved to be effective in patients with glioblastoma or high grade anaplastic glioma when administered with concurrent radiotherapy either as adjuvant or recurrent settings
Temozolomide has been known to deplete O6-methylguanine DNA methyltransferase MGMT which is one of the DNA repair enzymes and recent studies have shown that MGMT gene silencing lower expression by immunohistochemistry or hypermethylation by methylation-specific PCR played a predictive marker of better responses to CRT with temozolomide in patient with glioblastoma and high grade anaplastic glioma
Silencing of MGMT by promoter hypermethylation has been known to involve colorectal carcinogenesis pathway by the association with KRAS mutation and low-CIMP CpG island methylation phenotype and microsatellite instability There have been suggestions that MGMT promoter hypermethylation played a role as a predictive factor of low recurrence in colorectal cancer patients with adjuvant oral fluoropyrimidine chemotherapy after curative surgery and also as a predictive factor for treatment response from temozolomide in patients with metastatic colorectal cancer
Therefore combination chemotherapy of temozolomide plus capecitabine for rectal cancer patients when treated with preoperative CRT is worthy of investigated especially in those harbouring silenced MGMT gene as following reasons
1 the role of temozolomide has been well established
2 MGMT gene silencing is associated with colorectal carcinogenesis and might act as a predictive biomarker and
3 the addition of temozolomide can be synergistic during preoperative CRT with capecitabine for rectal cancer patients
Investigator have performed a phase I study of preoperative CRT with temozolomide plus capecitabine in patient with locally advanced rectal cancer and the results of this study has been published The recommended dose of temozolomide was determined as 75 mgm2 once daily when combined with standard preoperative CRT with capecitabine there was no grade 4 adverse events and the treatment was generally well tolerated MGMT hypermethylation was found in 72 of rectal cancer patients 1622 and the pathologic complete responses rates were 375 616 in patient harbouring hypermethylated MGMT versus 167 in those with unmethylated MGMT
On the basis of prior trial results Investigator concluded that preoperative CRT with temozolomide plus capecitabine is well tolerated without any notable adverse event and is worthy of investigation especially in those harbouring MGMT gene silencing
Investigator planned a prospective biomarker-stratified randomised phase II study of preoperative CRT with temozolomide plus capecitabine in patients with locally advanced rectal cancer to demonstrate the addition of temozolomide in the conventional preoperative CRT might enhance the pathologic responses in those harbouring hypermethylated MGMT
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None